The cellular and molecular mechanisms underlying long-term neuronal survival in the inner ear remain poorly understood. Histopathological correlations have suggested that hair cells are a critical source of survival signals for the VIIIth nerve. However, our work indicates that supporting cells in both cochlear and vestibular epithelia play key roles in neuronal maintenance via the neuregulin 1-erbB receptor and neurotrophin-Trk signaling pathways. Postnatal loss of erbB signaling in supporting cells leads to neuronal degeneration, preceded by a specific loss of NT3 in the cochlea and BDNF in the vestibular organs, at a time when these neurotrophins (NTs) are expressed primarily by supporting cells. Since erbB receptor signaling induces NT expression in other non-neuronal cells, and since inner ear sensory neurons express NRG1, we hypothesize that: NRG1, produced by cochlear and vestibular sensory neurons, induces supporting cells to express NTs, NT3 in the organ of Corti and BDNF in the vestibular epithelia. These NTs, acting back on the neurons, maintain their synaptic contacts with hair cells, induce their survival and preserve their function. We will test this hypothesis using genetically modified mice. In Aim 1, inducible cell-specific knockouts will test if elimination of either NT3 or BDNF in supporting cells or hair cells causes neuronal degeneration and inner ear dysfunction;and conditional cell-specific overexpression transgenics will test if the neuronal degeneration caused by loss of erbB signaling in supporting cells can be rescued by increasing NT expression. In Aim 2, we evaluate inner hair cell contributions to long-term neuronal maintenance using mice lacking the high-affinity thiamine transporter such that dietary thiamine restriction leads to widespread and selective loss of inner hair cells, without damage to supporting cells. Inner ear tissues will be quantitatively assessed over time by confocal morphometry of hair cell synapses and sensory ganglion cells, functional tests of evoked responses, and assessment of gene levels/patterns of expression of key trophic factors and their receptors using RT-PCR and in situ hybridization. Comparison of phenotypes obtained when controlling the up- or down-regulation of NT3 vs. BDNF in hair cells vs. supporting cells at different post-natal ages will provide insights into the specific roles of each neurotrophin, the cells involved in the signaling pathways, and the age-dependence of neuronal susceptibility to trophic factor deprivation. These experiments will provide important insights into the pathogenesis and potential treatment of sensorineural hearing loss and peripheral balance disorders. Progressive dysfunction of the inner ear is an important health issue. In spite of the high incidence of hearing and balance disorders, the cellular and molecular mechanisms that contribute to the long-term integrity of inner ear structure and function remain poorly understood. This project will investigate the cellular and molecular mechanisms involved in the long-term survival and function of inner ear sensory neurons using transgenic mouse models.